Streptococcus equi (S. equi subsp. equi) is a gram-positive coccus that has a large capsule. S. equi is the causative agent of strangles in equine, canine and Camelids, notably in horses, donkeys, mules, dogs, camels and dromedaries. Strangles is a highly contagious infection of the upper respiratory tract and associated lymph nodes. In equine, the disease is characterized by fever, thick mucopurulent nasal discharge, swelling and abscessation of the submandibular, submaxillary, and retropharyngeal lymph nodes. In severe cases, the infection may become disseminated with internal and external abscess formation and may ultimately result in death. It can occur in susceptible horses of any age. Transmission occurs through direct contact or indirectly through fomites that have been contaminated by respiratory tract secretions or saliva. Although rare, S. equi is a very serious zoonotic pathogen of Camelids (Sechi L A et al., New Microbiol, 1999, 22(4): 383-387), of humans infected by contact with horses (Elsayed S et al., Clin Microbiol Infect, 2003, 9(8): 869-872). In human, mortality was high (25%), especially among older patients and patients with endocarditis, meningitis and disseminated infection (Bradley S F et al., Rev Infect Dis, 1991, 13(2): 270-280; Popescu G A et al., South Med J, 2006, 99(2): 190-191).
After infection, S. equi generally has an incubation period 3 to 14 days before the onset of clinical signs. The organism rapidly translocates the mucosa into the lymphatic channels and from there moves to one or more of the regional lymph nodes leading to inflammation and swelling.
The enlarging lymph nodes soon develop purulent centers with fluctuant liquefaction. Submandibular lymph nodes typically rupture externally through the skin, whilst abscesses formed in the retropharyngeal lymph nodes typically rupture into the guttural pouch. This may take up to 2 weeks to occur after the onset of signs.
The majority (70%) of animals are immune to further attacks of strangles after recovery from a first infection. However, a substantial proportion of animals (30%) can contract the disease a second time, and of these a small proportion can contract the disease more than twice (Todd A. G., J. Comp. Pathol. Ther., 1910, 23, 212-229). Up to 10% of affected animals continue to shed S. equi intermittently for prolonged periods after clinical signs have resolved. This carrier state is probably caused by incomplete drainage of exudate from the guttural pouches (empyaema) and/or sinuses following rupture of abscesses formed in the retropharyngeal lymph nodes (Newton J R et al., Vet Record, 1997, 140: 84-90). Drying and hardening of exudate leads to the formation of discrete bodies called chondroids that can remain in the guttural pouch for several years. It is becoming increasingly recognised around the world that sub-clinical persistent carriage of S. equi is fundamental to the persistence of this infection between outbreaks (Fintl C et al., Vet Record, 2000, 147: 480-484; Newton J R et al., Vet Record, 1997, 140: 84-90; Newton J R et al., Equine Vet J, 2000, 32: 515-526; Timoney J F et al., Vet Record, 1998, 142: 648) and this remains true despite the advent of modern vaccines (Newton R et al., Vet Record, 2005, 156: 291-292).
Protection against the disease is primarily mediated by antibodies of the IgA and IgG subclasses locally produced in the nasopharynx.
Serum antibodies to Streptococcus equi (S. equi) can be measured by a variety of assays including ELISA (Reif et al., Proc. Am. Assoc. Equine Practitioners, 1982, 27, 33-40), the mouse protection test (Bazely P. L., Aust. Vet. J., 1943, 19, 62-85), and the gel diffusion precipitin test.
Commercially available vaccines consisting of heat-inactivated bacterin or M-protein-rich extracts have been widely used in the field. Although effective in stimulating serum bactericidal antibodies, these vaccines apparently do not stimulate a useful level of nasopharyngeal antibody and so the level of protection stimulated in a horse population is disappointing. An avirulent, genetically modified strain of S. equi administered intranasally has recently been shown to stimulate local nasopharyngeal antibodies similar to those found in convalescent immune horses. Vaccinated horses were immune to subsequent experimental challenge with virulent S. equi (Timoney and Galan, 1985, The protective response of the horse to an avirulent strain of Streptococcal equi. In Y. Kimura, S. Kotami and Y. Shokawa, eds., Recent Advances in Streptococci and Streptococcal disease. Reedbooks, Surrey, England, p. 294-295). It therefore appears that an effective strangles vaccine must be able to stimulate a nasopharyngeal immune response.
Bacterin-type vaccines aften cause undesirable local and systemic reactions consisting of edema, induration, stiffness, transient fever, and neutrophilia, effects that are probably due to cell wall peptidoglycan. Furthermore, purpura hemorrhagica can develop after vaccination of horses previously sensitised to streptococcal antigens.
Streptococcus zooepidemicus (S. equi subsp. zooepidemicus) is an important cause of respiratory disease and metritis in equine. S. zooepidemicus is an opportunist pathogen that causes purulent respiratory infections of weanling and yearling horses and uterine infections in elderly mares. In the situation of concurrent influenza infection high temperature or transport stress, it can be a devasting and rapid fatal pathogen in the respiratory tract. Although rare, S. zooepidemicus is a very serious zoonotic pathogen of Camelids (Younan M et al., J Vet Med B Infect Dis Vet Public Health, 2005, 52(3): 142-146), of humans infected by contact with horses (Downar J et al., J Clin Microbiol, 2001, 39(6): 2358-2359; Ural O et al., Scand J Infect Dis, 2003, 35(3): 206-207) and of canine animals having respiratory disease, notably already infected by Bordetella bronchiseptica (Chalker V J et al., Vet Microbiol, 2003, 95(1-2): 149-156).
S. equi affected mammals may harbor the bacteria for several months in, among other places, the guttoral pouches and, thus, shed and act as reservoirs of S. equi. Although S. equi is quite sensitive to penicillin and other antibiotics, antibiotic treatment is for various reasons mostly ineffective. In order to combat the disease and mitigate serious clinical complications, research has mainly been aimed at developing efficient vaccines.
The development of vaccines has been slow, possibly in part, because vaccines must be able to control infection without inducing a marked inflammatory response.
It is therefore desirable to develop vaccines having a high degree of immunogenicity and which exhibit a good safety profile with limited or no side effects.
Citation or identification of any document in this application is not an admission that such document is available as prior art to the present invention.